Normorphinans, which contain NH groups, are key intermediates for synthesizing important opioids such as naltrexone, naloxone, nalbuphine, nalmefene, and buprenorphine. Typically, normorphinans are prepared by the N-demethylation of N-methyl morphinans such as morphine, hydrocodone, or oxycodone. For this, the N-methyl morphinan generally is reacted with a hydrocarbyl chloroformate to form a normorphinan carbamate. Such demethylation reactions, however, tend to be unreliable, e.g., often failing to go to completion and requiring large excesses of the chloroformate and an added insoluble base. Thus, there is a need for more reliable and more efficient demethylation reactions during the preparation of normorphinans.
The preparation of normorphinans further comprises hydrolysis of the normorphinan carbamate to form the normorphinan. While carbamates can be readily hydrolyzed under acidic conditions, it is often necessary to conduct the hydrolysis under basic conditions in order to preserve acid sensitive functionalities, such as enol ethers, which may be present in the morphinan structure. The hydrolysis at high pH values requires high temperatures, typically above the boiling point of water at atmospheric pressure, which requires the use of pressurized reaction vessels made of corrosion-resistant material. Accordingly, there is a need for milder hydrolysis conditions (i.e., neutral pH levels, lower temperatures) for the removal of the carbamate functionality during the preparation of normorphinans.